tbuckley/cabot-search huggingface dataset:
Development and Validation of a Deep Learning–Based Synthetic Bone-Suppressed Model for Pulmonary Nodule Detection in Chest Radiographs
Authors: Hwiyoung Kim, Kye Ho Lee, Kyunghwa Han, Ji Won Lee, Jin Young Kim, Dong Jin Im, Yoo Jin Hong, Byoung Wook Choi, Jin Hur
Journal: JAMA Network Open (2023)

Importance Dual-energy chest radiography exhibits better sensitivity than single-energy chest radiography, partly due to its ability to remove overlying anatomical structures. Objectives To develop and validate a deep learning–based synthetic bone-suppressed (DLBS) nodule-detection algorithm for pulmonary nodule detection on chest radiographs. Design, Setting, and Participants This decision analytical modeling study used data from 3 centers between November 2015 and July 2019 from 1449 patients. The DLBS nodule-detection algorithm was trained using single-center data (institute 1) of 998 chest radiographs. The DLBS algorithm was validated using 2 external data sets (institute 2, 246 patients; and institute 3, 205 patients). Statistical analysis was performed from March to December 2021. Exposures DLBS nodule-detection algorithm. Main Outcomes and Measures The nodule-detection performance of DLBS model was compared with the convolution neural network nodule-detection algorithm (original model). Reader performance testing was conducted by 3 thoracic radiologists assisted by the DLBS algorithm or not. Sensitivity and false-positive markings per image (FPPI) were compared. Results Training data consisted of 998 patients (539 men [54.0%]; mean [SD] age, 54.2 [9.82] years), and 2 external validation data sets consisted of 246 patients (133 men [54.1%]; mean [SD] age, 55.3 [8.7] years) and 205 patients (105 men [51.2%]; mean [SD] age, 51.8 [9.1] years). Using the external validation data set of institute 2, the bone-suppressed model showed higher sensitivity compared with that of the original model for nodule detection (91.5% [109 of 119] vs 79.8% [95 of 119]; P &amp;amp;lt; .001). The overall mean of FPPI with the bone-suppressed model was reduced compared with the original model (0.07 [17 of 246] vs 0.09 [23 of 246]; P &amp;amp;lt; .001). For the observer performance testing with the data of institute 3, the mean sensitivity of 3 radiologists was 77.5% (95% [CI], 69.9%-85.2%), whereas that of radiologists assisted by DLBS modeling was 92.1% (95% CI, 86.3%-97.3%; P &amp;amp;lt; .001). The 3 radiologists had a reduced number of FPPI when assisted by the DLBS model (0.071 [95% CI, 0.041-0.111] vs 0.151 [95% CI, 0.111-0.210]; P &amp;amp;lt; .001). Conclusions and Relevance This decision analytical modeling study found that the DLBS model was more sensitive to detecting pulmonary nodules on chest radiographs compared with the original model. These findings suggest that the DLBS model could be beneficial to radiologists in the detection of lung nodules in chest radiographs without need of the specialized equipment or increase of radiation dose.
Neutrophil CEACAM1 determines susceptibility to NETosis by regulating the S1PR2/S1PR3 axis in liver transplantation
Authors: Hirofumi Hirao, Hidenobu Kojima, Kenneth J. Dery, Kojiro Nakamura, Kentaro Kadono, Yuan Zhai, Douglas G. Farmer, Fady M. Kaldas, Jerzy W. Kupiec-Weglinski
Journal: Journal of Clinical Investigation (2023)

Neutrophils, the largest innate immune cell population in humans, are the primary proinflammatory sentinel in the ischemia-reperfusion injury (IRI) mechanism in orthotopic liver transplantation (OLT). Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CC1, or CD66a) is essential in neutrophil activation and serves as a checkpoint regulator of innate immune-driven IRI cascade in OLT. Although CC1 alternative splicing generates two functionally distinct short and long cytoplasmic isoforms, their role in neutrophil activation remains unknown. Here, we undertook molecular and functional studies to interrogate the significance of neutrophil CC1 signaling in mouse and human OLT recipients. In the experimental arm, we employed a mouse OLT model to document that ablation of recipient-derived neutrophil CC1-long (CC1-L) isotype aggravated hepatic IRI by promoting neutrophil extracellular traps (NETs). Notably, by regulating the S1P-S1PR2/S1PR3 axis, neutrophil CC1-L determined susceptibility to NET formation via autophagy signaling. In the clinical arm, liver grafts from 55 transplant patients selectively enriched for neutrophil CC1-L showed relative resistance to ischemia-reperfusion (IR) stress/tissue damage, improved hepatocellular function, and clinical outcomes. In conclusion, despite neutrophils being considered a principal villain in peritransplant tissue injury, their CC1-L isoform may serve as a regulator of IR stress resistance/NETosis in human and mouse OLT recipients.
A Crystal-Independent Role for Uric Acid in AKI Associated with Tumor Lysis Syndrome
Authors: Abutaleb A. Ejaz, Rajesh Mohandas, Thomas M. Beaver, Richard J. Johnson
Journal: Journal of the American Society of Nephrology (2023)

Arnaud et al.1 make the important finding that AKI in tumor lysis syndrome (TLS) may occur in the absence of crystals, suggesting that other mechanisms may contribute to kidney damage besides the well-established mechanisms resulting from urate crystalluria with intratubular crystal precipitation. While these authors provide tantalizing evidence that extracellular histones may contribute to AKI by causing endothelial injury, we would also like to note that hyperuricemia in the absence of crystal deposition can also cause endothelial dysfunction, inflammation with the activation of inflammasomes, renal vasoconstriction, and reduced renal blood flow and GFR. In the cisplatin model of renal injury, hyperuricemia in the absence of crystal deposition exacerbated the renal injury, leading to local inflammation and worse kidney function.2 Modest elevations in serum uric acid have also been found to predict AKI from numerous causes, including after contrast administration, after cardiovascular surgery, and in TLS.3 Uric acid demonstrated linear correlation with serum creatinine and inverse correlation with kinetic eGFR in several clinical models. Pilot clinical trials suggest that lowering uric acid in subjects with mild to moderate hyperuricemia can reduce AKI (biomarkers) following cardiovascular surgery.4 In TLS, lowering uric acid attenuated rise in serum creatinine, decreased the incidence of AKI, and improved GFR. In a meta-analysis of 11 studies, treatment with allopurinol was associated with a significant increase in endothelium-dependent vasodilatation (even in asymptomatic patients with normal renal function), decrease in serum creatinine, and improvement in GFR. In the current study, serum uric acid levels in patients with TLS, TLS-AKI, and non-AKI TLS were 8.36 mg/dl, 8.74 mg/dl, and 6.79 mg/dl, respectively. However, the majority of patients with AKI did not have crystalluria. There were no crystal deposits in TLS mice due to the presence of uricase in the mice liver that degrades uric acid into allantoin. These observations are consistent with a crystal independent role for uric acid in AKI. More studies need to evaluate noncrystalline drives of AKI in TLS. New detective work suggests that extracellular histones represent some of the criminals. We would suggest that soluble uric acid is also an accomplice. We recommend more studies to investigate the role of urate lowering therapy in AKI.
Unwind to the beat: chromatin and cardiac conduction
Authors: Douglas J. Chapski, Thomas M. Vondriska
Journal: Journal of Clinical Investigation (2023)

How chromatin accessibility and structure endow highly specialized cells with their unique phenotypes is an area of intense investigation. In the mammalian heart, an exclusive subset of cardiac cells comprise the conduction system. Many molecular components of this system are well studied and genetic variation in some of the components induces abnormal cardiac conduction. However, genetic risk for cardiac arrhythmias in human populations also occurs in noncoding regions. A study by Bhattacharyya, Kollipara, et al. in this issue of the JCI examines how chromatin accessibility and structure may explain the mechanisms by which noncoding variants increase susceptibility to cardiac arrhythmias. We discuss the implications of these findings for cell type-specific gene regulation and highlight potential therapeutic strategies to engineer locus-specific epigenomic remodeling in vivo.
Unlocking life-threatening COVID-19 through two types of inborn errors of type I IFNs
Authors: Jean-Laurent Casanova, Mark S. Anderson
Journal: Journal of Clinical Investigation (2023)

Since 2003, rare inborn errors of human type I IFN immunity have been discovered, each underlying a few severe viral illnesses. Autoantibodies neutralizing type I IFNs due to rare inborn errors of autoimmune regulator (AIRE)-driven T cell tolerance were discovered in 2006, but not initially linked to any viral disease. These two lines of clinical investigation converged in 2020, with the discovery that inherited and/or autoimmune deficiencies of type I IFN immunity accounted for approximately 15%-20% of cases of critical COVID-19 pneumonia in unvaccinated individuals. Thus, insufficient type I IFN immunity at the onset of SARS-CoV-2 infection may be a general determinant of life-threatening COVID-19. These findings illustrate the unpredictable, but considerable, contribution of the study of rare human genetic diseases to basic biology and public health.
Making In Vitro Tumor Models Whole Again
Authors: Kenny Zhuoran Wu, Christabella Adine, Aleksandr Mitriashkin, Benjamin Jun Jie Aw, N. Gopalakrishna Iyer, Eliza Li Shan Fong
Journal: Advanced Healthcare Materials (2023)

As a reductionist approach, patient-derived in vitro tumor models are inherently still too simplistic for personalized drug testing as they do not capture many characteristics of the tumor microenvironment (TME), such as tumor architecture and stromal heterogeneity. This is especially problematic for assessing stromal-targeting drugs such as immunotherapies in which the density and distribution of immune and other stromal cells determine drug efficacy. On the other end, in vivo models are typically costly, low-throughput, and time-consuming to establish. Ex vivo patient-derived tumor explant (PDE) cultures involve the culture of resected tumor fragments that potentially retain the intact TME of the original tumor. Although developed decades ago, PDE cultures have not been widely adopted likely because of their low-throughput and poor long-term viability. However, with growing recognition of the importance of patient-specific TME in mediating drug response, especially in the field of immune-oncology, there is an urgent need to resurrect these holistic cultures. In this Review, the key limitations of patient-derived tumor explant cultures are outlined and technologies that have been developed or could be employed to address these limitations are discussed. Engineered holistic tumor explant cultures may truly realize the concept of personalized medicine for cancer patients.
BPDE, the Migration and Invasion of Human Trophoblast Cells, and Occurrence of Miscarriage in Humans: Roles of a Novel <i>lncRNA-HZ09</i>
Authors: Mengyuan Dai, Wenxin Huang, Xinying Huang, Chenglong Ma, Rong Wang, Peng Tian, Weina Chen, Ying Zhang, Chenyang Mi, Huidong Zhang
Journal: Environmental Health Perspectives (2023)

Background: Recurrent miscarriage (RM) affects 1%–3% of pregnancies. However, in almost 50% of cases, the cause is unknown. Increasing evidence have shown that benzo(a)pyrene [B(a)P], a representative of polycyclic aromatic hydrocarbons (PAHs), is correlated with miscarriage. However, the underlying mechanisms of B(a)P/benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE)-induced trophoblast cell dysfunctions and miscarriage remain largely unknown. Objective: The objective was to discover the role(s) of a novel lncRNA, lnc-HZ09, in the regulation of BPDE-inhibited migration and invasion of trophoblast cells and the occurrence of miscarriage. Method: Human trophoblast cells were treated with 0, 0.25, 0.5, 1.0, or 1.5μM BPDE with or without corresponding lnc-HZ09 silencing or overexpression. Using these cells, we evaluated cell migration and invasion, the mRNA and protein levels of members of the PLD1/RAC1/CDC42 pathway, the regulatory roles of lnc-HZ09 in PLD1 transcription and mRNA stability, and lnc-HZ09 transcription and stability. Human villous tissues were collected from RM (n=15) group and their matched healthy control (HC, n=15) group. We evaluated the levels of BPDE-DNA adducts, lnc-HZ09, and the mRNA and protein expression of members of the PLD1/RAC1/CDC42 pathway, and correlated their relative expression levels. We further constructed 0, 0.05 or 0.2mg/kg B(a)P-induced mouse miscarriage model (each n=6), in which the mRNA and protein expression of members of the Pld1/Rac1/Cdc42 pathway were measured. Results: We identified a novel lnc-HZ09. Human trophoblast cells treated with lnc-HZ09 exhibited less cell migration and invasion. In addition, the levels of this lncRNA were higher in villous tissues from women with recurrent miscarriage than those from healthy individuals. SP1-mediated PLD1 mRNA levels were lower, and HuR-mediated PLD1 mRNA stability was less in trophoblast cells overexpressing lnc-HZ09. However, trophoblast cells treated with MSX1 had higher levels of lnc-HZ09, and METTL3-mediated m6A methylation on lnc-HZ09 resulted in greater lnc-HZ09 RNA stability. In BPDE-treated human trophoblast cells and in RM villous tissues, MSX1-mediated lnc-HZ09 transcription and METTL3-mediated lnc-HZ09 stability were both greater. In our mouse miscarriage model, B(a)P-treated mice had lower mRNA and protein levels of members of the Pld1/Rac1/Cdc42 pathway. Discussion: These results suggest that in human trophoblast cells, BPDE exposure up-regulated lnc-HZ09 level, suppressed PLD1/RAC1/CDC42 pathway, and inhibited migration and invasion, providing new insights in understanding the causes and mechanisms of unexplained miscarriage. https://doi.org/10.1289/EHP10477
Evaluation of Comparative Efficacy and Safety of Surgical Approaches for Total Hip Arthroplasty
Authors: Lei Yan, Long Ge, Shengjie Dong, Kiran Saluja, Dijun Li, K. Srikanth Reddy, Qi Wang, Liang Yao, Jiao Jiao Li, Bruno Roza da Costa, Dan Xing, Bin Wang
Journal: JAMA Network Open (2023)

Each approach for primary total hip arthroplasty (THA) has a long learning curve, so a surgeon's choice to change their preferred approach needs to be guided by clear justifications. However, current evidence does not suggest that any of the THA approaches are more beneficial than others, and the choice of approach is mainly based on the knowledge and experience of the surgeon and individual patient characteristics.
Avoid being trapped by your liver: ischemia-reperfusion injury in liver transplant triggers S1P-mediated NETosis
Authors: Davide Scozzi, Andrew E. Gelman
Journal: Journal of Clinical Investigation (2023)

Liver transplantation can be a life-saving treatment for end-stage hepatic disease. Unfortunately, some recipients develop ischemia-reperfusion injury (IRI) that leads to poor short- and long-term outcomes. Recent work has shown neutrophils contribute to IRI by undergoing NETosis, a form of death characterized by DNA ejection resulting in inflammatory extracellular traps. In this issue of the JCI, Hirao and Kojima et al. report that sphingosine-1-phosphate (S1P) expression induced by liver transplant-mediated IRI triggers NETosis. They also provide evidence that neutrophil expression of the carcinoembryonic antigen-related cell adhesion molecule-1 (CC1) long isoform inhibited NETosis by controlling S1P receptor-mediated autophagic flux. These findings suggest stimulating regulatory mechanisms that suppress NETosis could be used to prevent IRI.
The global syndemic of metabolic diseases in the young adult population: A consortium of trends and projections from the Global Burden of Disease 2000–2019
Authors: Bryan Chong, Gwyneth Kong, Kannan Shankar, H.S. Jocelyn Chew, Chaoxing Lin, Rachel Goh, Yip Han Chin, Darren Jun Hao Tan, Kai En Chan, Wen Hui Lim, Nicholas Syn, Siew Pang Chan, Jiong-Wei Wang, Chin Meng Khoo, Georgios K. Dimitriadis, Karn Wijarnpreecha, Arun Sanyal, Mazen Noureddin, Mohammad Shadab Siddiqui, Roger Foo, Anurag Mehta, Gemma A. Figtree, Derek J. Hausenloy, Mark Y. Chan, Cheng Han Ng, Mark Muthiah, Mamas A. Mamas, Nicholas W.S. Chew
Journal: Metabolism (2023)
Tobacco, Alcohol, Cannabis, and Other Drug Use in the US Before and During the Early Phase of the COVID-19 Pandemic
Authors: Wilson M. Compton, Kerry S. J. Flannagan, Marushka L. Silveira, MeLisa R. Creamer, Heather L. Kimmel, Moana Kanel, Carlos Blanco, Nora D. Volkow
Journal: JAMA Network Open (2023)

Importance Information about national substance use trends among youths and adults after mid-March 2020 is limited due to constraints on surveillance during the COVID-19 pandemic. Objective To evaluate whether substance use prevalence in the early part of the pandemic (2020) differed from the prepandemic periods of 2018 to 2019 and 2016 to 2018. Design, Setting, and Participants This cross-sectional study was a repeated analysis of 2016 to 2020 data from a nationally representative sample of youths and adults in the Population Assessment of Tobacco and Health (PATH) Study. Participants were representative of the US civilian noninstitutionalized population. Household residents age 13 years or older were interviewed in person from 2016 to 2019 and via telephone in 2020. Exposures Age, calendar year. Main Outcomes and Measures Past 30-day self-reported use of any tobacco, any alcohol, binge drinking, cannabis, and any other illegal or misused prescription drugs. Results The overall nationally representative 2020 sample included 7129 youths (ages 13-17 years), 3628 young adults (ages 18-20 years), and 8874 adults (ages ≥21 years). Comparing 2018 to 2019 with 2020 among youths, prevalence of all substances used declined (eg, cannabis use declined in those aged 16-17 years from 14.9% to 7.6%; absolute difference, −7.3 percentage points [95% CI −8.8 to −5.8 percentage points]). Among young adults, prevalence of all substances other than any alcohol decreased significantly (eg, tobacco use declined from 37.8% to 22.8%; absolute difference, −15.1 percentage points [95% CI −16.8 to −13.3 percentage points]). In adults ages 21 to 24 years, any tobacco use declined from 39.0% to 30.9% (absolute difference, −8.2 percentage points [95% CI, −10.6 to −5.7 percentage points]), and alcohol use increased from 60.2% to 65.2% (absolute difference, 5.0 percentage points [95% CI, 2.3 to 7.7 percentage points]). Among adults aged 25 years or older, any tobacco use declined from 39.0% to 30.9% (absolute difference, −8.2 percentage points [95% CI, −10.6 to −5.7 percentage points]), cannabis use increased from 11.3% to 12.4% (absolute difference, 1.2 percentage points [95% CI, 0.3 to 2.0 percentage points]), and other substance use declined from 5.8% to 3.7% (absolute difference, −2.1 percentage points [95% CI, −2.9 to −1.4 percentage points]). Conclusions and Relevance In this cross-sectional study, substance use decreased between 2019 and 2020 among those aged 13 to 20 years; consistent declines were not seen in older persons other than tobacco use reductions, and cannabis use increased among adults ages 25 years and older. While social changes during the COVID-19 pandemic could have affected substance use, findings should be interpreted with caution due to differences in data collection methods in 2016 to 2019 and 2020.
Estimated Carbon Emissions Savings With Shifts From In-Person Visits to Telemedicine for Patients With Cancer
Authors: Krupal B. Patel, Brian D. Gonzalez, Kea Turner, Amir Alishahi Tabriz, Dana E. Rollison, Edmondo Robinson, Cristina Naso, Xuefeng Wang, Philippe E. Spiess
Journal: JAMA Network Open (2023)

Importance While the health care community advocates broadly for climate change policy, medical professionals can look within care practices to assess their contribution to carbon dioxide (CO 2 ) emissions, and provide solutions wherever possible. Telemedicine can help in mitigating climate change by providing care from a distance. Objective To assess the carbon savings achieved from telemedicine visits. Design, Setting, and Participants This cross-sectional study of telemedicine visits was conducted at a single-institution National Cancer Institute (NCI)-designated comprehensive cancer center. Eligible patients were aged 18 years and above, completed telemedicine visits from April 1, 2020, to June 20, 2021, and had a Florida mailing address documented in their electronic medical record. Groups were divided between those within driving time of 60 minutes (1-way) to the cancer center vs those living beyond 60 minutes of drive time. Data were analyzed between April 2020 and June 2021. Main Outcomes and Measures Carbon emission savings from telemedicine, measured in total and average per-visit savings. Results A total 49 329 telemedicine visits with 23 228 patients were conducted from April 1, 2020, to June 30, 2021. A total 21 489 visits were for patients with driving time of 60 minutes or less (median [IQR] age, 62.0 [52.0-71.0] years; 12 334 [57.4%] female; 1685 [7.8%] Black, 1500 [7.0%] Hispanic, 16 010 [74.5%] non-Hispanic White), while 27 840 visits were for patients with driving time greater than 60 minutes (median [IQR] age, 67.0 [57.0-74.0] years; 14 372 [51.6%] female; 1056 [3.8%] Black, 1364 [5.0%] Hispanic, 22 457 [80.7%] non-Hispanic White). For patients living within a driving time of 60 minutes from the cancer center, 424 471 kg CO 2 emissions were saved (mean [SD] emissions savings, 19.8 [9.4] kg CO 2 per visit) due to telemedicine—equivalent to 91.5 passenger vehicles driven for 1 year. For patients whose driving distance was greater than 60 minutes, 2 744 248 kg CO 2 emissions were saved (mean emissions savings, 98.6 [54.8] kg CO 2 per visit)—equivalent to 591 passenger vehicles driven for 1 year. Conclusions and Relevance Using a large data set, this cross-sectional analysis highlighted the carbon emissions savings due to telemedicine in oncology. This has important implications in reducing health care–related carbon footprint.
NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression
Authors: Yen-Po Tsao, Fang-Yu Tseng, Chih-Wei Chao, Ming-Han Chen, Yi-Chen Yeh, Babamale Olarewaju Abdulkareem, Se-Yi Chen, Wen-Ting Chuang, Pei-Ching Chang, I-Chun Chen, Pin-Hsuan Wang, Chien-Sheng Wu, Chang-Youh Tsai, Szu-Ting Chen
Journal: Journal of Clinical Investigation (2023)

Signaling driven by nucleic acid sensors participates in interferonopathy-mediated autoimmune diseases. NLRP12, a pyrin-containing NLR protein, is a negative regulator of innate immune activation and type I interferon (IFN-I) production. Peripheral blood mononuclear cells (PBMCs) derived from systemic lupus erythematosus (SLE) patients expressed lower levels of NLRP12, with an inverse correlation with IFNA expression and high disease activity. NLRP12 expression was transcriptionally suppressed by runt-related transcription factor 1-dependent (RUNX1-dependent) epigenetic regulation under IFN-I treatment, which enhanced a negative feedback loop between low NLRP12 expression and IFN-I production. Reduced NLRP12 protein levels in SLE monocytes was linked to spontaneous activation of innate immune signaling and hyperresponsiveness to nucleic acid stimulations. Pristane-treated Nlrp12-/- mice exhibited augmented inflammation and immune responses; and substantial lymphoid hypertrophy was characterized in NLRP12-deficient lupus-prone mice. NLRP12 deficiency mediated the increase of autoantibody production, intensive glomerular IgG deposition, monocyte recruitment, and the deterioration of kidney function. These were bound in an IFN-I signature-dependent manner in the mouse models. Collectively, we reveal a remarkable link between low NLRP12 expression and lupus progression, which suggests the impact of NLRP12 on homeostasis and immune resilience.